Process for making optically active alpha-amino ketones and selected novel optically active alpha-amino ketones

ABSTRACT

The invention includes selected novel optically active α-amino ketones which either are themselves useful or are intermediates for the preparation of known ketomethylene pseudopeptides useful as antibiotics, antibiotic enhancers, or enzyme inhibitors. Further, the present invention provides a method for dehydrogenation/asymmetrical hydrogenation to obtain essentially pure antipodes of ketomethylene pseudopeptides having two chiral centers.

BACKGROUND OF THE INVENTION

Peptides in which the —CONH— linkage has been replaced by the —COCH₂—isosteric moiety are known as ketomethylene pseudopeptides¹ having knownutility. For example, such ketomethylene pseudopeptides may be useful asantibiotics, antibiotic enhancers or enzyme inhibitors. Further, thisstructural modification has been used to make peptide-like moleculeswith improved metabolic stability.² This structural motif has beenemployed for the preparation of numerous enzyme inhibitors,³ and haseven been found as a natural product.⁴ There have been a number ofingenious methods developed for the preparation of this important classof compounds. By far the most common approach to the synthesis of thisclass of peptide isosteres is to ignore the issue of absolutestereochemistry.⁵ There are reports of possible solutions to thequestion of the absolute configuration of the N-terminal opticallyactive center.⁶ There is a singular report of a successful approach tothe preparation of ketomethylene pseudopeptides with absolutestereocontrol at both asymmetric centers.⁷

Inhibitor molecules based on the ketomethylene isostere have been foundto be potent inhibitors of ACE (angiotensin converting enzyme),²Substance P,^(3b) carboxypeptidase A,^(3c) carboxypeptidase A,^(3c) andHIV protease.⁸

The preparation of optically active alpha-amino ketones bydehydrogenation of racemic alpha-amino ketones and hydrogenation usingan asymmetric hydrogenation catalyst is disclosed fordehydroketomethylene pseudopeptides having an aromatic substituentadjacent the keto group in U.S. Pat. No. 4,277,420; East German.Application Nos. 280,527; 280,528; 280,529; 240,372 described incorresponding Derwent Abstract Numbers 90-362220/49, 90-362221/49,90-362222/49, 87-057083/09, respectively.

Additional references directed to optically pure optically activeintermediates include:

-   -   U.S. Pat. No. 4,912,221;    -   EP Application No. 90307750.1;    -   U.S. Pat. No. 4,906,773;    -   U.S. Pat. No. 4,916,252;    -   U.S. Pat. No. 4,316,847;    -   EP Application No. 89403599.7;    -   Japanese Number 3002152A described in WPI Acc No. 91-048825;    -   German Appl. No. 140-036 described in Derwent Abstract No.        34661C/20.

Disclosure for a rhodium di (1R, 2R)- or (1S,2S)-bis(phenyl-4-methoxyphenylphosphino)ethane (Rh DiPAMP) catalyst andits use as an enantioselective hydrogenation catalyst is exemplified ineach of the following:

-   -   J. Am. Chem. Soc. 1977(August 31), 99; 17 pp. 594652;    -   J. Am. Chem. Soc. 1977(September 6), 94:18 pp. 6429-33;    -   Synthesis 1979(May) pp. 350-2; and    -   Chem. Ber. 1981, 114, pp. 1137-49.

The present process takes advantage of the very practical method for thepreparation of optically active succinates⁹ as a key component for amodified Dakin-West reaction. This protocol effectively introduces theC-terminal optically active center with the appropriate D- or L-aminoacid absolute configuration at C-2. The Dakin-West reaction does nothowever offer a-method for the control of the N-terminal opticallyactive center at C-5. In an effort to control both asymmetric centers ofa ketomethylene pseudopeptide, the present invention provides a methodfor the dehydrogenation/asymmetric hydrogenation of certainketomethylene pseudopeptides. The invention is a novel synthetic methodfor the preparation of this class of peptide isostere in which bothasymmetric centers are fixed with known absolute configuration. Thepresent method permits the introduction of the C-5 optically activecenter with very high optical purity. In addition, since the absoluteconfiguration of the C-5 center is induced by the absolute configurationof the asymmetric catalyst ligand, it is possible to make either opticalantipode independently by the appropriate choice of ligand absoluteconfiguration.

The flexibility of our synthesis permits the synthesis of very uniqueanalogues of α-amino ketones that have improved biological propertiesrelative to molecules available by more demanding syntheses. Theliterature is replete with examples of novel amino acid side chainsdesigned to impart improved biological properties to these molecules.

BRIEF SUMMARY OF THE INVENTION

The present invention is a novel compound of the formula (I or I₁)

wherein

-   R₁ is hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an    aromatic group, preferably CH₂Ar, including, particularly,    unsubstituted or substituted phenylmethyl;-   R₂ is CH₂R₉ wherein R₉ is    -   (a) hydrogen,    -   (b) C₁-C₄ alkyl optionally substituted with one or more        hydroxyl, C₁-C₃ alkoxy, chloro, or fluoro,    -   (c) phenyl optionally substituted with one to three of C₁-C₄        alkyl, halogen where halogen is fluoro, chloro, bromo or iodo,        hydroxyl, nitro, C₁-C₃ alkoxy, or —CO—N(R₇)₂ wherein R₇ is,        independently, H or C₁-C₄ alkyl,    -   (d) a 5-7 member heterocycle such as pyridyl, furyl, indolyl or        benzisoxazolyl,    -   (e) C₃-C₇ cycloalkyl, or    -   (f) naphthyl;-   R₃ is    -   wherein one of R₆ and R₈ is hydrogen and the other is    -   (1) hydrogen;    -   (2) alkyl of from 1 to 6 carbons optionally substituted by one        or two hydroxyl, chloro or fluoro;    -   (3) cycloalkyl of from 3 to 7 ring carbons;    -   (4) Ar₄ which is a group such as phenyl, or phenyl substituted        by one to three substituent(s) consisting of        -   (a) alkyl of from one to four carbons,        -   (b) halogen consisting of fluoro, chloro, bromo, iodo,        -   (c) alkoxy of from one to three carbons,        -   (d) nitro,        -   (e) amido,        -   (f) mono- or di-alkyl (of from one to four carbons)amido, or        -   (g) hydroxy;    -   (5) Ar₅ which is tolyl;    -   (6) Ar₆ which is tolyl substituted by one to three substituents        consisting of        -   (a) alkyl of from of one to four carbons,        -   (b) halogen consisting of fluoro, chloro, bromo, iodo,        -   (c) alkoxy of from one to three carbons,        -   (d) nitro,        -   (e) amido,        -   (f) mono- or di-alkyl (of from one to four carbons) amido,            or        -   (g) hydroxy;    -   (7) Ar₇ which is a group optionally attached through a CH₂ and        is naphthyl or naphthyl substituted by one to three substituents        consisting of        -   (a) alkyl of from one to four carbons,        -   (b) halogen consisting of fluoro, chloro, bromo, iodo,        -   (c) alkoxy of from one to three carbons,        -   (d) nitro,        -   (e) amido,        -   (f) mono- or di-alkyl (of from one to four carbons) amido,            or        -   (g) hydroxy;    -   (8) Ar₈ which is a group such as indol-3-yl, indol-2-yl, or        imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or        imidazol-4-ylmethyl (preferably unsubstituted or substituted        phenyl or indol-3-yl);    -   (9) NHA wherein A is        -   (a) trityl,        -   (b) hydrogen,        -   (c) alkyl of from one to six carbons,        -   (d) R₁₀ CO wherein R₁₀ is (A)hydrogen, (B) alkyl of from one            to six carbons optionally substituted with hydroxyl, chloro,            or fluoro, (C) phenyl or naphthyl; unsubstituted or            substituted with one to three of (i) alkyl of from one to            three carbons, (ii) halogen where halogen is F, Cl, Br, or            I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to            three carbons, (vi) CON(R₁₁)₂ wherein R₁₁ is independently            hydrogen or alkyl of from one to four carbons, or (D) a 5 to            7 member heterocycle such as indolyl, pyridyl, furyl or            benzisoxazolyl;        -   (e) phthaloyl wherein the aromatic ring is optionally            substituted by one to three of (A) alkyl of from one to            three carbons, (B) halogen where halogen is F, Cl, Br, or            I, (C) hydroxy, (D) nitro, (E) alkoxy of from one to three            carbons, (F) CON(R₁₁)₂ wherein R₁₁ is independently hydrogen            or alkyl of from one to four carbons,        -   (f) R₁₂(R₁₃R₁₄C)_(m)CO wherein m is one to three and R₁₂,            R₁₃, and R₁₄ are independently (A) hydrogen, (B) chloro or            fluoro, (C) alkyl of from one to three carbons optionally            substituted by chloro, fluoro, or hydroxy, (D) hydroxy, (E)            phenyl or naphthyl optionally substituted by one to three            of (i) alkyl of from one to three carbons, (ii) halogen            where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv)            nitro, (v) alkoxy of from one to three carbons, (vi)            CON(R₁₁)₂ wherein R₁₁ is independently hydrogen or alkyl of            from one to four carbons, (F) alkoxy of from one to three            carbons, (G) 5 to 7 member heterocycle such as pyridyl,            furyl, or benzisoxazolyl, or (H)R₁₂,R₁₃ and R₁₄ are            independently joined to form a monocyclic, bicyclic, or            tricycle ring system each ring of which is a cycloalkyl of            from three to six carbons, except that only one of R₁₂, R₁₃            and R₁₄ can be hydroxy or alkoxy on the same carbon and can            not be hydroxy, chloro or fluoro when m is one;        -   (g) R₁₂(R₁₃R₁₄C)_(m)W wherein m is independently 1 to 3 and            W is OCO or SO₂ and R₁₂, R₁₃, and R₁₄ are independently as            defined above;        -   (h) R₂₀W wherein R₂₀ is a 5 to 7 member heterocycle such as            pyridyl, furyl, or benzisoxazolyl;        -   (i) R₂₁W wherein R₂₁ is phenyl or naphthyl unsubstituted or            substituted by one to three substituents of (i) alkyl of            from one to three carbons, (ii) halogen where halogen is F,            Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from            one to three carbons, (vi) CON(R₁₁)₂ wherein R₁₁ is            independently hydrogen or alkyl of from one to four carbons;        -   (j) R₁₂(R₁₃R₁₄C)_(m)P(O) (OR₂₂) wherein R₂₂ is alkyl of from            one to four carbons or phenyl;        -   (k) R₂₀P(O)(OR₂₂) wherein R₂₂ is as defined above;        -   (l) R₂₁P(O)(OR₂₂) wherein R₂₂ is as defined above;-   N(R₁₁)₂ wherein R₁₁ is independently as defined above;    -   (10) R₁₂(R₁₃R₁₄C)_(m)V wherein V is O or NH and R₁₂(R₁₃R₁₄ are        independently as defined above;    -   (11) N(R₁₁)₂ wherein R₁₁ is independently as defined above;    -   (12) NR₁₅NR₁₆ wherein R₁₅ and R₁₆ are joined to form a 4 to 6        membered saturated nitrogen containing heterocycle which is (a)        azetidinyl, (b) pyrrolidinyl, (c) piperidinyl, or (d)        morpholinyl;    -   (13) R₁₇OCH₂O wherein R₁₇ is        -   (a) alkyl of from one to six carbons,        -   (b) R₂₁ wherein R₂₁ is independently defined as above; or        -   (c) CH₂Q₁ wherein Q₁ is phenyl, naphthyl or a 5 to 7            membered heterocycle;    -   (14) R₁₇OCH₂CH₂OCH₂ wherein R₁₇ is independently as defined        above;    -   (15) alkynyl of from two to six carbons optionally substituted        with R₂₁ where in R₂₁ is independently as defined above;    -   (16) alkenyl of from two to six carbons optionally substituted        with R₂₁ where in R₂₁ is independently as defined above;-   R₅ is independently hydrogen, alkyl, lower cycloalkyl, or an    aromatic group, preferably unsubstituted or substituted phenyl;-   R₄ is hydrogen, an amino acid radical or a protecting group such as    a substituted or unsubstituted acyl;-   R₅ is hydrogen, alkyl, lower cycloalkyl, or ar wherein ar is an    aromatic group, preferably unsubstituted or substituted phenyl.

The present invention is also a process for the treatment of a compoundof the formula (II or II₁)

wherein R₁ and R₂ is as defined above;

-   R₃′ is    wherein R₆ is as defined above; and-   R₈′ is hydrogen, C₁-C₄ alkyl or cycloalkyl with the proviso that one    of R₆ or R₈′ is hydrogen;-   R₄′ is a protecting group such as a substituted or unsubstituted    acyl or amino acid radical;-   R₅′ is hydrogen;    -   with hydrogen in the presence of rhodium (R,R)-(1,2-ethanediyl        bis[ortho-methoxyphenyl)phenylphosphine] (H₂RhDiPAMP) in        deoxygenated solvent;    -   optionally deprotecting the nitrogen or deprotecting the        nitrogen and further treating to add an amino acid radical to        the nitrogen to obtain a compound of the formula I or I₁ wherein        R₁, R₂, R₃, R₄, R₅, and R₆ are as defined above.

The present invention is a compound of the formula (II or II₁)

wherein R₁, R₂, R₃′, R₄′ and R₅ are as defined above.

The present invention is also the preparation of a compound of theformula II or II₁ as defined above comprising the treatment of thecompound of the formula (III or III₁)

wherein R₁, R₂, R₃′, R₄′ and R₅′ are as defined above; withtertiary-butyl hypochlorite and 1,4-diazabicyclo[2.2.2]octane (DABCO) toobtain a compound of the formula II or II₁.

DETAILED DESCRIPTION OF THE INVENTION

C₁-C₃ or —C₄ means alkyl of from one to three or four such as methyl,ethyl, propyl or butyl and isomers thereof and the like.

Protection of the amino group can be accomplished by methods well knownto those familiar with amino acid chemistry. For example, the aminogroup be protected utilizing a carbonyl compound represented by theformula

wherein R′ represents alkyl radicals having from 1 to about 10 carbonatoms, and aryl, aralkyl and alkaryl radicals having from about 6 toabout 26 carbon atoms; or aryl or alkylaryl or aralkyl with suitablecarbon numbers, A represents oxygen; n is 0 or 1; and Q represents Cl,Br, I, or C(O)A_(n)R′ wherein R′, A and n have the same meanings asdefined above. Exemplary amino protecting groups are acyl groupsincluding such groups as acetyl, benzoyl, formyl, propionyl, butyryl,toluyl and may include substituted such groups, for example,nitrobenzoyl, and the like. In other words, the amino protecting groupsare those commonly used as blocking groups in peptide synthesis.

C₃-C₇ cycloalkyl means cyclic hydrocarbon groups containing 3 to 7carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methyl cylopentyl, methyl cyclohexyl, dimethyl cyclopentyl, cycloheptyland the like.

Ar is an aromatic group which means a phenyl, substituted phenyl, tolyl,substituted tolyl, naphthyl and the like.

Substituted phenyl and substituted tolyl means from one to threesubstituents such as alkyl, carboxyl, hydroxyl (and base salts thereof),alkoxy, halogen which means fluoro, chloro, bromo, or iodo, C₂-C₄acyloxy, aryloxy, aralkoxy, amino, alkyl amido (both mono and dialkylamido), nitro, cyano.

Optically active means the compound includes at least one opticallyactive carbon.

Generally, the process comprising the treatment of the compound offormula II or II₁ with hydrogen in the presence of DiPAMP to obtain thecompound of the formula I or I₁ respectively is as set out hereinafter.The reaction is accomplished at from about 1 to 100 psig and at atemperature from about 0° C. to 60° C. preferably at about roomtemperature and at a pressure about 40 psig, in inert solvents such asmethanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile andthe like or mixtures thereof.

Evaluation of the results may be accomplished by standard methods, suchas vapor phase chromatography on a optically active capillary column, orby HPLC (high performance liquid chromatography) on a optically activecolumn or by evaluation of the optical rotation of a solution of thecompound.

A Fisher-Porter bottle is charged with the appropriate substratedissolved in deoxygenated methanol along with 0.1-1.0 mol percentrhodium (R, R)-DiPAMP (R,R)-(1,2-ethanediylbis[(o-methoxyphenyl)phenylphosphine]. After 5 nitrogen purges (40 psig)the solution was purged 5 times with hydrogen (40 psig) and then allowedto hydrogenate at room temperature for 1-24 h. The hydrogen is replacedwith nitrogen and the contents of the bottle concentrated in vacuo. Thecatalyst residue is separated from the optically active ketomethylenepseudopeptides I or I₁ by dissolving the product in iso-octane. Thecatalyst residue is not soluble in iso-octane.

A general procedure for the hydrolysis of optically active N,O-protectedketomethylene pseudopeptides of the formula I or I₁ wherein R₄′ is aprotecting group is as follows. A sample of the optically activeN,O-protected ketomethylene pseudopeptide derivative is refluxed for 24h with 12 N hydrochloric acid. The solvent is removed in vacuo. Theresidue is taken up in water and re-concentrated in vacuo. Afterthoroughly drying under vacuum the hydrochloride salt is converted tothe free amine by treatment with excess propylene oxide. Theprecipitated amino acid is then isolated by filtration and optionallyrecrystallized from water/methanol.

An evaluation is made of optical purity by optically active vapor phasechromatography. The N,O-protected optically active ketomethylenepseudopeptide derivatives are analyzed by optically active gaschromatography for optical purity. A solution of the racemicketomethylene pseudopeptide derivative in dichloromethane is separatedinto the two enantiomers by a 25 meter Chirasil Val III capillary columnwith flame ionization detection. After conditions for separation of thetwo enantiomers are established, each optically active hydrogenationproduct is evaluated for the extent of optical purity.

Generally, the compound of the formula II or II₁ are prepared by themethod shown in Scheme 2 hereinafter.

The conditions of the treatment of formula III or III₁ by tertiary-butylhypochlorite are at a temperature of 0° C.-50° C. in an inert solventsuch as dichloromethane, chloroform, acetonitrile and the like Theproduct of this treatment is then further treated with1,4-diazabicyclo[2.2.2]octane (DABCO) at a temperature of 0° C.-50° C.in an inert solvent such as dichloromethane, tetrahydrofuran,chloroform, acetonitrile and the like.

Compounds of the formula III or III₁ are prepared by methods known inthe art or by methods analogous to those known in the art from startingmaterial which are known or which can be prepared by known methods.

Variations in these conditions and evaluations for different compoundswithin the definitions of the formula I or I₁ are within the skill of anordinarily skilled artisan.

The general procedure for removal of a protecting group, such as thetert-butyl ester is as follows. A sample of the product, I and I₁, isdissolved in dichloromethane and treated with an equal (volume) amountof trifluoroacetic acid at 0° C. The solution is allowed to warm to roomtemperature and the progress of the reaction monitored by TLC. When thereaction is finished the solvents are removed in vacuo and the residuepurified by crystallization or flash chromatography on silica gel.

The compounds of the Formula I or I₁ are useful as intermediates in thepreparation of pharmacologically active compounds. It is contemplatedthat certain intermediates disclosed herein will manifest similaractivity.

The compounds of Formula I or I₁ which manifest pharmacologically activeare useful both in the free base and the free acid form or in the formof base salts thereof, as well as, in the form of acid addition salts.All forms are within the scope of the invention. In practice, use of thesalt form amounts to use of the free acid or free base form. Appropriatepharmaceutically acceptable salts within the scope of the invention arethose derived from mineral and organic acids or those derived from basessuch as suitable organic and inorganic bases. For example, see“Pharmaceutical Salts”, J. Pharm. Sci., 66(1), 1-19 (1977). The acidaddition salts of said compounds are prepared either by dissolving thefree base of compound I or I₁ in aqueous or aqueous alcohol solution orother suitable solvents containing the appropriate acid or base andisolating the salt by evaporating the solution, or by reacting the freebase of Compound I or I₁ with an acid as well as reacting compound I orI₁ having an acid group thereon with a base such that the reactions arein an organic solvent, in which case the salt separates directly or canbe obtained by concentration of the solution.

The base salts of compounds of Formula I or I₁ described above areprepared by reacting the appropriate base with a stoichiometricequivalent of the acid compounds of Formula I or I₁ to obtainpharmacologically acceptable base salts thereof.

Contemplated equivalents of the general formulas set forth above for thecompounds I or I₁ as well as the compounds useful to prepare compounds Ior I₁ are compounds otherwise corresponding thereto and having the samegeneral properties wherein one or more of the various R groups aresimple variations of the substituents as defined therein, e.g., whereinR₂ or R₃ is a higher alkyl group. In addition, where a substituent isdesignated as, or can be, a hydrogen, the exact chemical nature of asubstituent which is other than hydrogen at that position is notcritical so long as it does not adversely affect the overall activityand/or synthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of. the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1 Part 1. Preparation of 2(R), 5(S)N-acetyl-Phe[COCH₂]Ala—OMe

Step 1. Cyclodehydration of N-benzoyl D,L-phenylalanine with aceticanhydride: General method for the preparation of alpha-amino acidoxazolones. A 100 mL round bottomed flask is charged with N-benzoylD,L-phenylalanine (6.75 g, 25.1 mmol) and 50 mL of acetic anhydride. Thecontents of the flask are warmed to 100 C for 1 h and then the excessacetic anhydride is removed in vacuo. The oily residue thus produced istaken up in boiling hexanes, filtered, and allowed to stand undisturbedwhereupon white crystals of pure product forms which are isolated byfiltration and further dried in vacuo to give 4.48 g, 71% of pureoxazolone, mp 70-71 C.

Step 2. Preparation of N-acetyl 2(R), 5(R,S)-Phe[COCH₂]Ala—OMe;methyl-5(R,S)-N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate.

A 250 mL round-bottomed flask was charged withN-acetyl-D,L-phenylalanine oxazolone (9.40 g, 72.5 mmol), 2-methylmono-methylsuccinate (10.68g, 73.2 mmol) and 50 mL of chloroform. Thesolution was treated with 4-dimethylaminopyridine (1.00 g, 8.18 mmol),and triethylamine (7.80 g, 77.2 mmol) and then stirred at roomtemperature for 72 h. The solution was concentrated in vacuo and theresidue dissolved in ethyl acetate, the solution was washed with 3N HCl,sat. aq. NaHCO₃, brine, dried over anhyd. MgSO₄, filtered andconcentrated to give an orange oil. This crude product was purified bychromatography on a Waters Prep-500 instrument over 2 silica gelcartridges eluting with hexanes/ethyl acetate. The appropriate fractionswere combined and concentrated to give the desired ketomethylene as a1:1 mixture of diastereomers at C-5, 8.20 g, 40.8%.

Step 3. Preparation of methyl N-acetyl-2(R)-methyl-4-keto-6-phenylhex-5-eneoate.

A 25 mL one-necked round-bottomed flask was equipped with a magneticstir bar, nitrogen inlet, and reflux condenser was charged with methyl5(R,S)-N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate (200 mg, 0.88mmol) and 13 mL of chloroform. To this solution was added tert-butylhypochlorite (250 mg, 2.90 mmol) via syringe. The solution was stirredat room temperature of 5 minutes and then the progress of the reactionevaluated by thin layer chromatography (TLC) on silica gel eluting with1:1 hexane:ethyl acetate, the starting material had R_(f)=0.32 and theN-chloro intermediate had an R_(f)=0.84. After 1.5 h the reaction wascomplete and the solution was then concentrated in vacuo and redissolvedin the minimum amount of benzene. The benzene solution of the N-chlorointermediate was then added to a solution of1,4-diazabicyclo[2.2.2]octane (330 mg, 2.95 mmol) in 20 mL of benzene.This solution was stirred at room temperature for 1.5 h and thenevaluated by TLC on silica gel eluting with 1:1 hexane:ethyl acetatewhich showed that the starting material was gone and the desired producthad been formed, R_(f)=0.40. The solution was diluted with ethyl acetateand poured into a separatory funnel and washed with 3N HCl, sat. aq.NaHCO₃, brine, dried over anhyd. MgSO₄, filtered and concentrated togive methyl N-acetyl-2(R)-methyl-4-keto-6-phenyl hex-5-eneoate as anoil, which was used directly in the next step.

Step 4. Asymmetric hydrogenation of methylN-acetyl-2(R)-methyl-4-keto-6-phenyl hex-5-eneoate: Preparation ofmethyl 5(S)-N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate.

A Fisher-Porter bottle was charged with 30 mL of degassed methanol andthe crude product from Step 2 along with rhodium (R,R)-DiPAMP (15 mg,0.02 mmol). The solution was flushed 5 times with nitrogen and 5 timeswith hydrogen and hydrogenated at 40 psig for 24 h. The bottle wasopened and the solution concentrated in vacuo to give the crude productwhich was separated from the catalyst by radial chromatography on silicagel eluting with 20% ethyl acetate in hexane to give 170 mg, 85% ofmethyl 5(S)-N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate, TLC onsilica gel eluting with 1:1 hexane:ethyl acetate R_(f)=0.33, ¹H and ¹³Cnmr showed that only one diastereomer was present.Part II. Verification of the Absolute Configuration.

Step 5. Acidic hydrolysis of methyl5(R,S)—N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate: Preparation of5(S)-N-amino-2(R)-methyl-4-keto-6-phenyl hexanoic acid hydrochloride.

A 100 mL round-bottomed flask equipped with a reflux condenser wascharged with methyl 5(R,S)-N-acetyl-2(R)-methyl-4-keto-6-phenylhexanoate (4.15 g, 15 mmol), 30 mL of conc. HCl, and 15 mL of glacialacetic acid. The solution was warmed to 95° C. for 16 h, then cooled toroom temperature washed 2 times with ether and the aqueous phaseconcentrated in vacuo to give 3.90 g, of a white powder, 96%. The crudeproduct was then dissolved in acetonitrile, however some material didnot dissolve. The insoluble material, 650 mg, was examined by ¹H and ¹³Cnmr which showed that it was a single diastereomer, mp 162-164° C. dec.

Step 2. Preparation of5(S)-N-(1,1-dimethylethoxycarbonylamino)-2(R)-methyl-4-keto-6-phenylhexanoic acid from 5(S)-amino-2(R)-methyl-4-keto-6-phenyl hexanoic acidhydrochloride.

A portion of this pure diastereomer (200 mg, 0.74 mmol) was placed in a50 mL Erlenmeyer flask and diluted with 10 mL of dioxane and 10 mL of0.1N NaOH. The above solution was then treated with a solution ofdi-tert-butylpyrocarbonate (185 mg, 0.85 mmol) in 2 mL of dioxane. ThepH of the solution was maintained at 8.5 by the periodic addition of0.1N NaOH. When the pH stabilized, ca. 2 h, the pH of the solution wasadjusted to 3.0 by the addition of 1N KHSO₄ and then extracted 4 timeswith ethyl acetate. The combined ethyl acetate extracts were washed withbrine, dried over anhyd. MgSO₄, filtered and concentrated in vacuo togive a white crystalline solid. This material was then recrystallizedfrom hexane ethyl acetate to give pure5(S)-N-(1,1-dimethylethoxycarbonylamino)-2(R)-methyl-4-keto-6-phenylhexanoic acid, mp 126.0-127.5° C., 162 mg, 69%. These crystals weresuitable for single crystal X-ray crystallography which confirmed thatthe absolute configuration was 2(R), 5(S).

Step 3. Preparation of methyl 5(S)-N-acetyl-2(R)-methyl-4-keto-6-phenylhexanoate.

A sample of the single diastereomer from Step 1 was converted to methyl5(S)-N-acetyl-2(R)-methyl-4-keto-6-phenyl hexanoate by acetylation withacetic anhydride followed by esterification with methyl iodide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The material prepared in thismanner was identical to the material prepared in Part 1, Step 3,confirming the 2(R),5(S) absolute configuration of the material preparedin Part 1, Step 3.

References and Notes

-   ¹ Spatola, A. F., Chemistry and Biochemistry Amino Acids, Peptides,    and Proteins. Weinstein, B.; Marcel Dekker, New York, 1983, pp    267-357.-   ². Almquist, R. G.; Olsen, C. M.; Uyeno, E. T.; Toll, L. J. Med.    Chem., 1984, 27, 115.-   ³ (a) Almquist, R. G., Chao, W. R.; Ellis, M. E.; Handsom, H. L. J.    Med. Chem., 1980, 23, 1392, (b) Ewenson, A.; Laufer, R.; Chorev, M.;    Selinger, Z.; Gilom, C., J. Med. Chem., 1986, 29, 295, (c) Shohom,    G.; Christianson, W.; Oren, D. A. Proc. Natl. Acad. Sci. USA, 1988,    85, 684, (d) Ewenson, A.; Laufer, R.; Chorev, M.; Selinger, Z.;    Gilom, C. J. Med. Chem., 1988, 31, 416.-   ⁴ Ohuchi, S.; Suda, H.; Naganawa, H.; Takita, T.; Aoyagi, T.;    Umezawa, H.; Nakamura, H.; Litaka, Y., J. Antibiot., 1983, 36, 1576.-   ⁵ (a) Garcia-Lopez, M. T.; Gonzalez-Muniz, R.; Harto, J. R.    Tetrahedron Lett., 1988, 29, 1577, (b) Meyer, R. F.; Essemburg, A.    D.; Smith, R. D.; Kaplan, H. R. J. Med. Chem., 1982, 25, 996, (c)    Almquist, R. G.; Crase, J.; Jennings-White, C.; Meyer, R. F.;    Hoefle, M. L.; Smith, R. D.; Essenburg, A. D.; Kaplan, H. R. J. Med.    Chem., 1982, 25, 1292, (d) McMurray, J. S.; Dyckes, D. F. J. Org.    Chem., 1985, 50, 1112, (e) Ewenson, A.; Cohen-Suissa, R.;    Levian-Teitelbaum, D.; Selinger, Zl; Chorev, M.; Gilon, C. Int. J.,    Peptide Protein Res., 1988, 31, 269, (f) Almquist, R. G.; Olsen, C.    M.; Uyeno, E. T.; Toll, L. J. Med. Chem., 1984, 24, 115.-   ⁶ (a) Johnson, R. L.; Miller, R. B. Int. J. Peptide Protein Res.,    1984, 23, 581, (b) Jennings-White, C.; Almquist, R. G. Tetrahedron    Lett., 1982, 23, 2533.-   ⁷ Holladay, M.; Rich, D. H. Tetrahedron Lett., 1983, 24, 4401.-   ⁸ Marshall, G. R. Washington University, St. Louis, Mo. has    incorporated certain ketomethylene pseudopeptides into inhibitors of    HIV-1 protease of U.S. Pat. No. 5,086,165, Feb. 2, 1992. Some of    these key optically active intermediates were supplied by the    inventor.-   ⁹ Talley, J. J. U.S. Pat. No. 4,939,288, Jul. 3, 1990.

1. A novel compound of the formula (I or I₁)

or a pharmaceutically acceptable salt thereof; wherein R₁ is hydrogen,alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group; R₂ isCH₂R₉ wherein R₉ is (a) hydrogen, (b) C₁-C₄ alkyl optionally substitutedwith one or more hydroxyl, C₁-C₃ alkoxy, chloro, or fluoro, (c) phenyloptionally substituted with one to three of C₁-C₄ alkyl, halogen wherehalogen is fluoro, chloro, bromo or iodo, hydroxyl, nitro, C₁-C₃ alkoxy,or —CO—N(R₇)₂ wherein R₇ is, independently, H or C₁-C₄ alkyl, (d) a 5-7member heterocycle such as pyridyl, furyl, indolyl or benzisoxazolyl,(e) C₃-C₇ cycloalkyl, or (f) naphthyl; R₃ is

wherein one of R₆ and R₈ is hydrogen and the other is (1) hydrogen; (2)alkyl of from 1 to 6 carbons optionally substituted by one or twohydroxyl, chloro or fluoro; (3) cycloalkyl of from 3 to 7 ring carbons;(4) Ar₄ which is a group such as phenyl, or phenyl substituted by one tothree substituent(s) consisting of (a) alkyl of from one to fourcarbons, (b) halogen consisting of fluoro, chloro, bromo, iodo, (c)alkoxy of from one to three carbons, (d) nitro, (e) amido, (f) mono- ordi-alkyl (of from one to four carbons) amido, or (g) hydroxy; (5) Ar₅which is tolyl; (6) Ar₆ which is tolyl substituted by one to threesubstituents consisting of (a) alkyl of from one to four carbons, (b)halogen consisting of fluoro, chloro, bromo, iodo, (c) alkoxy of fromone to three carbons, (d) nitro, (e) amido, (f) mono- or di-alkyl (offrom one to four carbons) amido, or (g) hydroxy; (7) Ar₇ which isnaphthyl or naphthyl substituted by one to three substituents consistingof (a) alkyl of from one to four carbons, (b) halogen consisting offluoro, chloro, bromo, iodo, (c) alkoxy of from one to three carbons,(d) nitro, (e) amido, (f) mono- or di-alkyl (of from one to fourcarbons) amido, or (g) hydroxy; or (8) Ar₈ which is indol-3-yl,indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl orimidazol-4-ylmethyl; (9) NHA wherein A is (a) trityl, (b) hydrogen, (c)alkyl of from one to six carbons, (d) R₁₀CO wherein R₁₀ is (A)hydrogen,(B) alkyl of from one to six carbons optionally substituted withhydroxyl, chloro, or fluoro, (C) phenyl or naphthyl unsubstituted orsubstituted with one to three of (i) alkyl of from one to three carbons,(ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv)nitro, (v) alkoxy of from one to three carbons, (vi) CON(R₁₁)₂ whereinR₁₁ is independently hydrogen or alkyl of from one to four carbons, or(D) a 5 to 7 member heterocycle such as indolyl, pyridyl, furyl orbenzisoxazolyl; (e) phthaloyl wherein the aromatic ring is optionallysubstituted by one to three of (A) alkyl of from to three carbons, (B)halogen where halogen is F, Cl, Br, or I, (C) hydroxy, (D) nitro, (E)alkoxy of from one to three carbons, (F) CON(R₁₁)₂ wherein R₁₁ isindependently hydrogen or alkyl of from one to four carbons, (f)R₁₂(R₁₃R₁₄C)_(m)Co wherein m is one to three and R₁₂, R₁₃, and R₁₄ areindependently (A) hydrogen, (B) chloro or fluoro, (C) alkyl of from oneto three carbons optionally substituted by chloro, fluoro, or hydroxy,(D) hydroxy, (E) phenyl or naphthyl optionally substituted by one tothree of (i) alkyl of from to three carbons, (ii) halogen where halogenis F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one tothree carbons, (vi) CON(R₁₁)₂ wherein R₁₁ is independently hydrogen oralkyl of from one to four carbons, (F) alkoxy of from one to threecarbons, (G) 5 to 7 member heterocycle such as pyridyl, furyl, orbenzisoxazolyl, or (H)R₁₂, R₁₃, and R₁₄ are independently joined to forma monocyclic, bicyclic, or tricycle ring system each ring of which is acycloalkyl of from three to six carbons, except that only one of R₁₂,R₁₃ and R₁₄ can be hydroxy or alkoxy on the same carbon and can not behydroxy, chloro or fluoro when m is one; (g) R₁₂(R₁₃R₁₄C)_(m)W wherein mis independently 1 to 3 and W is OCO or SO₂ and R₁₂R₁₃, and R₁₄ areindependently as defined above; (h) R₂₀W wherein R₂₀ is a 5 to 7 memberheterocycle; (i) R₂₁W wherein R₂₁ is phenyl or naphthyl unsubstituted orsubstituted by one to three substituents of (i) alkyl of from one tothree carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii)hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi)CON(R₁₁) wherein R₁₁ is independently hydrogen or alkyl of from one tofour carbons; (j) R₁₂(R₁₃R₁₄C)_(m)P(O) (OR₂₂) wherein R₂₂ is alkyl offrom one to four carbons or phenyl; (k) R₂₀P(O) (OR₂₂) wherein R₂₂ is asdefined above; (l) R₂₁P(O) (OR₂₂) wherein R₂₂ is as defined above;N(R₁₁)₂ wherein R₁₁ is independently as defined above; (10)R₁₂(R₁₃R₁₄C)_(m)V wherein V is O or NH and R₁₂(R₁₃R₁₄ are independentlyas defined above; (11) N(R₁₁)₂ wherein R₁₁ is independently as definedabove; (12) NR₁₅NR₁₆ wherein R₁₅ and R₁₆ are joined to form a 4 to 6membered saturated nitrogen containing heterocycle which is (a)azetidinyl, (b) pyrrolidinyl, (c) piperidinyl, or (d) morpholinyl; (13)R₁₇OCH₂O wherein R₁₇ is (a) alkyl of from one to six carbons, (b) R₂₁wherein R₂₁ is independently defined as above; or (c) CH₂Q₁ wherein Q₁is phenyl, naphthyl or a 5 to 7 membered heterocycle,; (14)R₁₇OCH₂CH₂OCH₂ wherein R₁₇ is independently as defined above; (15)alkynyl of from two to six carbons optionally substituted with R₂₁ wherein R₂₁ is independently as defined above; (16) alkenyl of from two tosix carbons optionally substituted with R₂₁ where in R₂₁ isindependently as defined above; R₄ is hydrogen, an amino acid radical ora protecting group; R₅ is independently hydrogen, alkyl, lowercycloalkyl, or Ar wherein Ar is an aromatic group. 2-14. (canceled)